Pharmaceutical composition comprising a peptide or a combination of peptides agonistic to the mas, at1 and at2 receptors

Abstract

The present invention relates to a peptide agonist of the Mas, AT1 and AT2 receptors, having amino acid sequence SEQ ID NO: 1, which is useful in preventing and / or treating hypertension, and / or reducing cardiovascular, cerebral, pulmonary and renal vasoconstriction, and / or preventing, reversing, inhibiting and / or reducing the pathological remodelling of cardiovascular, pulmonary, renal and / or cerebral tissue. The invention also relates to a pharmaceutical composition comprising the peptide or a combination of the peptides, useful in preventing and / or treating hypertension, reducing vascular vasoconstriction, and / or preventing, reversing, inhibiting and / or reducing the pathological remodelling of cardiovascular, pulmonary, renal and / or cerebral tissue.

Description

[0001] PHARMACEUTICAL COMPOSITION COMPRISING A PEPTIDE OR A COMBINATION OF AGONIST PEPTIDES OF THE MAS, AT1 AND AT2 RECEPTORS

[0002] TECHNICAL FIELD

[0003] The present invention relates to the technical field of the pharmaceutical industry, in particular, to peptide agonists of the Mas, AT1 and AT2 receptors, and a pharmaceutical composition comprising one or a combination of said peptides useful for preventing and / or treating hypertension, reducing vascular vasoconstriction, and / or preventing, reversing, inhibiting and / or reducing the pathological remodeling of cardiovascular, pulmonary, renal and / or cerebral tissues.

[0004] BACKGROUND

[0005] The renin-angiotensin system (RAS) is a hormonal system that regulates blood pressure and electrolyte homeostasis. It is composed of the angiotensin-converting enzyme (ACE) and its product, angiotensin II, which exerts its effects by binding to AT1 and AT2 receptors. Overstimulation of the RAS has pathophysiological effects such as hypertension, atherosclerosis, heart failure, coronary artery disease, and more.

[0006] There is a parallel pathway of the RAS mediated by the angiotensin I converting enzyme homolog (ACE2) that competes with ACE for the hydrolysis of angiotensin I to form angiotensin-(1 -9). Subsequently, angiotensin-(1 -9) is degraded by ACE to angiotensin-(1 -7). Angiotensin-(1 -7) is a peptide with antagonistic properties to the effects of angiotensin II: it induces vasodilation and has antihypertensive and antifibrotic effects (Padda RS, et al. Angiotensin-(1 - 7): A Novel Peptide to Treat Hypertension and Nephropathy in Diabetes? J Diabetes Metab. 2015. Vol. 6(10)). Likewise, the Mas receptor is a protein found on the surface of cells in many tissues of the body, including the heart and blood vessels. This receptor is an integral part of the RAS and plays an important role in regulating blood pressure through its interaction with angiotensin-(1-7).Angiotensin-(1 -7) binds to the Mas receptor, which causes a cascade that ultimately produces vasodilation (Santos, RA, Simoes e Silva, AC, Marie, C., Silva, DM, Machado, RP, de Buhr, I., ... & Campagnole-Santos, MJ Angiotensin-(1 -7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci. 2003. Vol. 100(14):8258-8263.

[0007] In turn, angiotensin-(1-9) also has opposite effects to angiotensin II: it lowers blood pressure and reduces cardiovascular damage. Chronic administration of angiotensin-(1-9) to hypertensive rats has been shown to reduce systolic and diastolic blood pressure, improve cardiac and endothelial function, as well as cardiovascular remodeling and oxidative stress (Ocaranza MP, etal. Angiotensin-(1-9) reverses experimental hypertension and cardiovascular damage by inhibition of the angiotensin converting enzyme / Ang II axis. J Hypertens. 2014. 32(4):771-83). Also, the administration of angiotensin-(1 -9) by using osmotic minipumps to rats infarcted by ligation of the left coronary artery, decreased cardiac hypertrophy, evaluated by the decrease in the levels of ANF (atrial natriuretic factor) mRNA, protein levels of [3-MHC (beta myosin heavy chain), and cardiomyocyte size (area and perimeter) (Ocaranza MP, et al.Angiotensin-(1 -9) regulates cardiac hypertrophy in vivo and in vitro. J Hypertens. 2010. 28(5):1054-64).

[0008] Although peptides have high bioactivity and high specificity with few or no side effects, as is the case with angiotensin-(1-9), most peptides are short-lived molecules because they are easily degraded by enzymes, with little or no therapeutic use. The high number of peptidases present in the blood makes their half-life in plasma very short. One strategy to design peptides stable to protease degradation is the synthesis of retro-enantio analogues, also called retroinverso, which consists of joining non-natural D-amino acids, unlike the original peptide composed of L-amino acids, and also reversing the order of the amino acids with respect to the original sequence, thus resulting, theoretically, in a peptide that contains an orientation of its side chains very similar to that of the original structure (Van Regenmortel MHV & Muller S. D-peptides as immunogens and diagnostic reagents. Curr Opin Biotechnol. 1998.Vol. 9(4):377-382). For example, patent application WO2022238734A1 discloses the synthesis and use of an angiotensin-(1 -9) analogue corresponding to a retro-enantio of angiotensin-(1 -9), which has greater stability and plasma half-life compared to native angiotensin-(1 -9) and, in turn, maintains the same biological activity as the peptide composed of L-amino acids.

[0009] Although the antihypertensive effects of the angiotensin-(1-9) retro-enantio peptide have been demonstrated, this may not be sufficient, considering that most patients with hypertension need a combination of at least two conventional drugs to normalize their blood pressure levels, and between 15 - 20% of patients require a combination of at least 3 drugs.

[0010] This background has raised the need to find alternatives to traditional antihypertensive treatments by developing dual or triple inhibitors, that is, those intended to inhibit enzymes involved in the generation of vasoconstrictor peptides or to act as blockers of receptors that trigger vasoconstrictor mechanisms.

[0011] SUMMARY OF THE INVENTION

[0012] A first object of the present invention corresponds to an agonist peptide of the Mas, AT1 and AT2 receptors, which comprises the amino acid sequence D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H LP (SEQ ID NO: 1 ). Said peptide is used for the prevention and / or treatment of hypertension, and / or to decrease vasoconstriction at the cardiovascular, cerebral, pulmonary and renal levels, and / or prevent, reverse, inhibit and / or reduce the pathological remodeling of cardiovascular, pulmonary, renal, and / or cerebral tissues, including, but not limited to, heart failure with preserved, moderately reduced or reduced ejection fraction (congestive heart failure, compensated heart failure, decompensated heart failure and the like), coronary and other arterial restenosis with atherosclerosis, arterial hypertension (essential hypertension, low-renin hypertension, salt-sensitive hypertension, low-renin salt-sensitive hypertension, resistant and refractory arterial hypertension, pregnancy-induced hypertension; primary pulmonary hypertension, thromboembolic pulmonary hypertension; renovascular hypertension), cardiac hypertrophy,diastolic dysfunction, coronary artery disease, myocardial infarctions, cerebral infarctions, atherosclerosis, atherogenesis, cerebrovascular disease, angina (including chronic, stable, unstable, and vagrant angina pectoris, aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or nonvascular complications associated with the use of medical devices, wounds associated with the use of medical devices, vascular or nonvascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiography, vascular grafting, artery bypass grafting or coronary artery bypass grafting, thromboembolic events, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation, or atrial flutter,thrombotic occlusion and cerebrovascular seclusion.,

[0013] Since this invention has anti-inflammatory properties, this peptide is used for the prevention and / or treatment of systemic and more localized diseases with inflammatory pathogenesis such as autoimmune and degenerative diseases with an inflammatory component (lupus erythematosus, rheumatoid arthritis, polymyositis, dermatomyositis, polymyalgia rheumatica, localized or systemic osteoarthritis). It is also used for liver diseases with inflammatory and fibrotic pathogenesis such as fatty liver or hepatic steatosis of different etiologies, chronic liver damage of different etiologies, liver cirrhosis of different etiologies, for respiratory diseases with inflammatory and fibrotic pathogenesis such as pulmonary fibrosis and / or chronic lung damage of different etiologies, for intestinal or digestive diseases with inflammatory and fibrotic pathogenesis such as Crohn's disease, ulcerative colitis, colon diverticulosis, plastic peritonitis

[0014] A second object of the present invention corresponds to a pharmaceutical composition comprising an agonist peptide of the Mas, AT 1 and AT2 receptors that includes the amino acid sequence D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1) and a pharmaceutically acceptable excipient; or a pharmaceutical composition comprising a combination of Mas, AT1 and AT2 receptor agonist peptides whose amino acid sequences include the amino acid sequence D H D F D P D H D Yo D AND D V D R D D (SEQ ID NO: 2) and the amino acid sequence

[0015] L D L R L V L AND L Yo L H LP (SEQ ID NO: 3) and a pharmaceutically acceptable excipient.

[0016] In a preferred embodiment of the present invention, the pharmaceutical composition includes the peptide of SEQ ID NO: 1 in a concentration between 10' 18 M and 10' 4 M.

[0017] In a preferred embodiment of the present invention, any of the above-described pharmaceutical compositions may additionally include angiotensin I converting enzyme inhibitors, angiotensin II receptor antagonists, Rho kinase inhibitors, diuretics, calcium channel inhibitors, renin inhibitors, beta-blockers, nephlysin inhibitors, dual angiotensin II receptor neprilysin antagonists, other retroinverso peptides, and other cardiovascular drugs such as SGLT2 inhibitors (used in the treatment of heart failure and diabetes) and myosin inhibitors (used in the treatment of hypertrophic cardiomyopathy). Here, the angiotensin I converting enzyme inhibitors include, but are not limited to, lisinopril, enalapril, captopril, zofenopril, ramipril, quinapril, perindopril, benazepril, and fosinopril.Here, angiotensin II receptor antagonists include, but are not limited to, valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan, and saralasin. Here, calcium channel inhibitors include, but are not limited to, dihydropyridines (nicardipine, nifedipine, amlodipine, felodipine, nitrendipine, nisoldipine, isradipine, nimodipine), benzothiazepines (diltiazem, clentiazem), and phenylalkylamines (verapamil, gallopamil, anipamil, RO5967, falipamil). In this document, Rho kinase inhibitors include, but are not limited to, fasudil, hydroxyfasudil, 3-(4-pyridyl)-1 H-indole, (S) (+) 2-methyl-1-[(4-methyl-5-20 isoquinolinyl) sulfonyl] homopiperazine, N-(4-pyridyl) N'(2,4,6-thchlorophenyl) urea.In this document, diuretics include, but are not limited to, thiazide diuretics (bendroflumethiazide, benzithiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, methyclothiazide, metolazone, polythiazide, quinethazone, trichloromethiazide, xipamide), loop diuretics (furosemide, torasemide, bumetanide, ethacrynic acid), carbonic anhydrase inhibitors (acetazolamide, dorzolamide), sodium channel inhibitors (amilohda, thamterene), aldosterone antagonists (spironolactone, canrenoate, eplerenone), and osmotic compounds (mannitol). Here, renin inhibitors include, but are not limited to, pepstatin, CGP2928, remikiren, enalkiren, zankiren, aliskiren. Here, dual angiotensin II and nephrotoxicity antagonists include, but are not limited to, sacubitril and valsartan. Selective nephrotoxicity inhibitors include, but are not limited to, acanthoxazole, dexecadotril, ecadotril, racecadotril, sacubritil, thiorphan, and UK-414,495.Non-selective nephlysin inhibitors include, but are not limited to, aladotril, alatriopril, daglutril, fasidotril, gemopathlat, ilepatril, ketalorphan, omapathlat, phosphoramidon, RB-101, sampathlat, spinorphan, tynorphin. Beta blockers include, but are not limited to, acebutolol, atenolol, bisoprolol, metaprolol, nadolol, nebivolol, propranolol. SGLT2 inhibitors include, but are not limited to, empagliflozin, dapagliflozin, canagliflozin. Myosin inhibitors include, but are not limited to, mevacamten, aficamten. Other retroinverse peptides herein include, but are not limited to, bradykinin retroinverso and AT1 R retroinverso.

[0018] In another preferred embodiment of the present invention, any of the pharmaceutical compositions described above are formulated for administration by oral, venous injection, intramuscular, intraperitoneal or continuous infusion by pump.

[0019] A third object of the present invention relates to the use of any of the pharmaceutical compositions or their preferred embodiments described above for the preparation of a medicament useful for preventing and / or treating hypertension; or for the preparation of a medicament useful for reducing vasoconstriction at the cardiovascular, cerebral, pulmonary, and renal levels; or for the preparation of a medicament useful for preventing, reversing, inhibiting, and / or reducing the pathological remodeling of cardiovascular, pulmonary, renal, and / or cerebral tissues.

[0020] A fourth object of the present invention corresponds to a method for preventing and / or treating hypertension comprising administering to a subject requiring it a therapeutically effective dose of any of the pharmaceutical compositions or their preferred embodiments described above. BRIEF DESCRIPTION OF THE FIGURES

[0021] FIG. 1 shows the result of the evaluation of the molecular identity of the peptide of SEQ ID NO: 1 by mass spectrometry.

[0022] FIG. 2 shows the results of the purity determination of the peptide of SEQ ID NO: 1 (also known as peptide HP16) by HPLC. The graphs show the elution time of said peptide.

[0023] FIG. 3 shows a graph showing the vasodilatory effect of angiotensin-(1-9) retro-inverse peptide (RI1-9) (referred to as RI1-9 in the figure) and peptide SEQ ID NO: 1 (referred to as HP16 in the figure). Data were expressed as mean ± SEM (n=28-30). ***p < 0.001 vs angiotensin-(1-9) retro-inverse peptide after the Mann-Whitney test.

[0024] FIG. 4 shows a graph showing the vasodilatory efficacy of the peptides angiotensin-(1-9) retro-inverso peptide (RI1-9) (referred to as RI1-9 in the figure) and SEQ ID NO: 1 (referred to as HP16 in the figure). ***p < 0.001 vs angiotensin-(1-9) retro-inverso peptide after the Mann-Whitney test, n=28-30.

[0025] FIG. 5 shows a graph showing the vasodilatory effect of the peptide of SEQ ID NO: 1 (referred to as HP16 in the figure) in the presence and absence of the angiotensin-(1-7) Mas receptor blocker, A779. Data were expressed as mean ± SEM (n=6-28). *p < 0.05; **p < 0.01; ***p < 0.001 vs the peptide of SEQ ID NO:1 + A779, followed by the Mann-Whitney test.

[0026] FIG. 6 shows a graph showing the vasodilatory effect of the peptide of SEQ ID NO: 1 (referred to as HP-16 in the figure) in the presence and absence of an AT2 receptor blocker, PD123319. Data were expressed as mean ± SEM (n=11-28). **p < 0.01 vs. the peptide of SEQ ID NO:1 + PD123319, followed by the Mann-Whitney test.

[0027] FIG. 7 shows a graph of the vasodilatory effect of the peptide of SEQ ID NO: 1 (called HP16 in the figure) in the presence and absence of Losartan. Data were expressed as mean ± SEM (n=8-28). *p < 0.05; **p < 0.01 vs peptide of SEQ ID NO: 1 + Losartan; *p < 0.05; **p < 0.01 vs peptide of SEQ ID NO:1, after the Mann-Whitney test. FIG. 8 shows a graph of the vasodilatory effect of the peptide of SEQ ID NO: 1 (called HP-16 in this figure) in the presence and absence of A779, PD123319 and Losartan. Data were expressed as mean ± SEM (n=8-28). *p < 0.05; **p < 0.01 vs the peptide of SEQ ID NO: 1 + Losartan + PD123319 + A779, after the Mann-Whitney test.

[0028] DETAILED DESCRIPTION OF THE INVENTION

[0029] The present invention comprises an agonist peptide (SEQ ID NO: 1) of the Mas, AT1, and AT2 receptors and pharmaceutical compositions comprising them. This peptide, by binding to the AT1 receptor, blocks the vasoconstrictor effect and tissue damage due to arrestin induction, and by binding to the AT2 and Mas receptors, it produces a vasodilatory, antihypertensive, and cardioprotective effect, and reduces tissue damage.

[0030] All technical and scientific terms used to describe this invention have the same meaning as understood by a person with basic knowledge in the technical field concerned. However, to more clearly define the scope of the invention, the terminology used in this description and its meaning are listed below.

[0031] The term “retro” refers to a peptide composed of D-amino acids in which the amino acids are assembled in the same direction as the native peptide.

[0032] The term “enantio” or “inverse” refers to a peptide that is made up of L-amino acids in which the amino acids are assembled in the opposite direction to the native peptide.

[0033] The term “retro-enantio” or “retro-inverso” refers to a peptide that is composed of D-amino acids in which the amino acids are assembled in the opposite direction to that of the native peptide.

[0034] The term "subject" shall be understood to mean any mammal such as humans, mice, rats, rabbits, primates, cats, dogs, among others, without being limited to those mentioned herein. The term "subject" shall be understood as a synonym for the term "individual" and shall be used interchangeably in this description. The term "treatment" shall be understood as a set or means that are used with a therapeutic action in a subject who has developed or is in the early stages of developing a disease, syndrome or condition. The treatment may be a treatment of the subject's symptoms with the purpose of alleviating their symptoms, it may refer to a treatment of the cause that originates the disease, syndrome or condition, with the purpose of reversing, delaying or stopping the progression of said disease, syndrome or condition.Therefore, the pharmaceutical composition of the present invention, as well as the methods described herein, can be used, for example, as therapeutic treatment methods for a specific period of time or chronically, as required by the subject. The term "treatment" also includes preventative treatments that involve treating subjects at risk of developing a disease, syndrome, or condition to reduce that risk.

[0035] The term "effective amount" or "therapeutically effective dose" refers to the dose and time period required to achieve the desired therapeutic result. The effective amount can depend on many factors, such as the stage of disease progression, the individual's age, sex, weight, the presence of other medical conditions, the simultaneous use of other medications, race, and other factors.

[0036] The term "hypertension" refers to any disease or disorder associated with high blood pressure, such as low-renin hypertension, salt-sensitive hypertension, salt-sensitive low-renin hypertension, primary pulmonary hypertension, thromboembolic pulmonary hypertension, pregnancy-induced hypertension, renovascular hypertension, and others.

[0037] The term "remodeling" refers to any complex change that organs and tissues undergo when subjected to stressful conditions. This term should be understood in its broadest possible sense and involves numerous cellular, biochemical, and / or physiological processes, including hypertrophy, fibrosis, inflammation, apoptosis, necrosis, autophagy, and oxidation, among others.

[0038] A first object of the present invention is an agonist peptide of the Mas, AT1 and AT2 receptors comprising or consisting of the amino acid sequence D HD F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1), which corresponds to a fusion of the retro-enantio peptide of angiotensin-(1-9) (D-amino acids, N-terminal to C-terminal direction: D H D F D P D H D Yo D AND D V D R D D (SEQ ID NO: 2)) and the peptide angiotensin-(1-7) (L-amino acids, N-terminal to C-terminal direction: L D L R L V L AND L Yo L H LP (SEQ ID NO: 3)). Surprisingly, the peptide of SEQ ID NO: 1 has a vasodilatory effect at a concentration 1000 times lower compared to the angiotensin-(1-9) retro-enantio peptide, and has an effective half-maximum concentration (ECso) an order of magnitude lower than the angiotensin-(1-9) retro-enantio peptide. In a preferred embodiment of the invention, the peptide of SEQ ID NO: 1 is used for the prevention and / or treatment of hypertension, and / or to decrease vascular vasoconstriction at the cardiovascular, cerebral, pulmonary and renal levels, and / or prevent, reverse, inhibit and / or reduce pathological remodeling of cardiovascular, pulmonary, renal, and / or cerebral tissues and / or induce cardioprotection.

[0039] The peptide of the present invention can be obtained by any method known in the state of the art, such as, for example, by the processes described in Goodman M et al. Methods of Organic Chemistry Vol. E 22, Supplement: Synthesis of Peptides and Peptidomimetics. Georg Thieme Verlag, 2004; and Chan, WC Fmoc solid phase peptide synthesis: a practical approach (Vol. 222). OUP Oxford, 1999, incorporated herein by reference, without being limited to those mentioned therein. For example, peptides can be synthesized by an azide process, an acid chloride process, an acid anhydride process, a mixed anhydride process, a DCC process, an active ester process (e.g., p-nitrophenyl ester, N-hydroxysuccinimide, or cyanomethyl ester), a carbodiimidazole process, an oxidative-reductive process, or a DCC / additive process. Such syntheses can be carried out in the solid phase or in the liquid phase.In a preferred embodiment of the present invention, the peptides are suitably prepared according to the above processes, such as those typically employed in peptide synthesis, generally by a step-by-step process comprising condensing an amino acid at the terminal amino acid, one by one in sequence, or by coupling peptide fragments to the terminal amino acid (amino acid side groups not used in the coupling reaction should be protected, e.g. with Fmoc, to prevent coupling at the wrong location). A second object of the present invention corresponds to a pharmaceutical composition comprising an agonist peptide of Mas, AT 1 and AT2 receptors including the amino acid sequence. D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H LP (SEQ ID NO: 1) and a pharmaceutically acceptable excipient.

[0040] In a preferred embodiment of the present invention, the pharmaceutical composition includes an effective amount of the peptide of SEQ ID NO: 1. Said effective amount may vary depending on multiple factors, as mentioned above. Preferably, the pharmaceutical composition includes the peptide of SEQ ID NO: 1 in a concentration between 10' and 10'. 18 M and 10' 4 M, preferably between 10' 15 M and 10' 13 M.

[0041] In another preferred embodiment, the peptide (SEQ ID NO: 1) of the present invention may be administered together or in co-administration with a cardiovascular therapeutic agent or drug known in the art. For example, the peptide may be co-administered with angiotensin I converting enzyme (ACE) inhibitors, with angiotensin II receptor antagonists or AT1 receptor blockers, with Rho kinase inhibitors, with renin inhibitors, calcium L channel antagonists, diuretics and / or with other retro-inverso peptides, and with other cardiovascular drugs thereof. Angiotensin I converting enzyme inhibitors include, but are not limited to, lisinopril, enalapril, captopril, zofenopril, ramipril, quinapril, perindopril, benazepril and fosinopril.Angiotensin II receptor antagonists or AT1 receptor blockers include, but are not limited to, valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan, and saralasin. Calcium L-channel antagonists include, but are not limited to, dihydropyridines (nicardipine, nifedipine, amlodipine, felodipine, nitrendipine, nisoldipine, isradipine, nimodipine), benzothiazepines (diltiazem, clentiazem), and phenylalkylamines (verapamil, gallopamil, anipamil, RO5967, falipamil). Rho kinase inhibitors include, but are not limited to, fasudil, hydroxyfasudil, 3-(4-pyridyl)-1 H-indole, (S)(+) 2-methyl-1-[(4-methyl-5-isoquinolinyl)sulfonyl] homopiperazine, N-(4-pyridyl) N'(2,4,6-thchlorophenyl) urea.Diuretics include, but are not limited to, thiazide diuretics (bendroflumethiazide, benzithiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, methyclothiazide, metolazone, polythiazide, quinethazone, trichloromethiazide, xipamide), loop diuretics (furosemide, torasemide, bumetanide), ethacrynic acid), carbonic anhydrase inhibitors (acetazolamide, dorzolamide), sodium channel inhibitors (amilohda, thamterene), aldosterone antagonists (spironolactone, canrenoate, eplerenone), and osmotic agents (mannitol). Renin inhibitors include, but are not limited to, pepstatin, CGP2928, remikiren, enalkiren, zankiren, aliskiren. Here, dual angiotensin II and neprilysin antagonists include, but are not limited to, sacubitl and valsartan. Selective neprilysin inhibitors include, but are not limited to, acandoxathl, dexecadothl, ecadotril, racecadothl, sacubritil, thiorphan, UK-414,495.Non-selective neprilysin inhibitors include, but are not limited to, aladotril, alatriopril, daglutril, fasidotril, gemopathlat, ilepatril, ketalorphan, omapathlat, phosphoramidon, RB-101, sampatrilat, spinorphan, tynorphin. Beta blockers include, but are not limited to, acebutolol, atenolol, bisoprolol, metaprolol, nadolol, nebivolol, propranolol. Other retro-inverso peptides include, but are not limited to, bradykinin retroinverso and AT1 R retroinverso.

[0042] The pharmaceutical composition of the present invention may be administered by all known routes of administration, preferably by injection and / or parenteral administration (e.g., intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, subcutaneous, direct injection into various organs, among others, but not limited to other alternatives), by inhalation, by continuous release pumps, suppositories, orally, among others, but not limited to those mentioned herein. Such administration may be in a single dose, multiple doses, or continuous administration.

[0043] The pharmaceutical composition of the present invention may be in liquid, solid, semi-solid form, or a mixture thereof, including tablets, wafers, dragees, caplets, capsules, pills, lozenges, powder, aqueous or oily suspensions, solutions, creams, ointments, coated formulations, sustained-release formulations, aerosols, micro and / or nanoparticles, among others, without being limited to those mentioned herein.

[0044] In other embodiments, pharmaceutical compositions containing the peptide, e.g., HP-16, generally contain an effective amount of the active compound together with a suitable amount of one or more carriers, stabilizers, diluents, excipients, and / or adjuvants, to enable preparation of the appropriate dose and form for administration of the peptide, e.g., HP-16, to the patient. In practicing the treatment methods of the invention, the particular dosage of a pharmaceutical composition or medicament to be administered to the subject will depend upon many variables including the disease state, the severity of the disease, the schedule of administration, the age, the physical characteristics of the subject, etc. Appropriate dosages can be established using clinical approaches as understood by those of skill in the art.The term "effective amount" refers to the dose and time period required to achieve the desired therapeutic result, i.e., to reduce tissue remodeling, increase cardioprotection, and effectively treat cardiovascular, kidney, and brain diseases. The effective amount can depend on many factors, such as the stage of disease progression, age, sex, and weight of the individual, the presence of other medical conditions, the use of other medications simultaneously, and race, among others.

[0045] As used herein, the term "cardiovascular disease" refers to any cardiovascular disease or disorder known in the art, including, but not limited to, heart failure (congestive heart failure, compensated heart failure, decompensated heart failure, and the like), restenosis, hypertension (low-renin hypertension; salt-sensitive hypertension; low-renin, salt-sensitive hypertension; primary pulmonary hypertension; thromboembolic pulmonary hypertension; pregnancy-induced hypertension; renovascular hypertension), cardiac hypertrophy, diastolic dysfunction, coronary artery disease, myocardial infarctions, infarcts, atherosclerosis, atherogenesis, cerebrovascular disease, angina (including chronic, stable, unstable, and vahant (Prinzmetal) angina), aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation,platelet adhesion, smooth muscle cell proliferation, vascular or non-vascular complications associated with the use of medical devices, wounds associated with the use of medical devices, vascular or non-vascular wall damage, peripheral vascular disease, neointimal hyperplasia following percutaneous transluminal coronary angiography, vascular grafting, coronary artery bypass surgery, thromboembolic events, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia, atrial fibrillation or atrial flutter, thrombotic occlusion and seclusion, cerebrovascular incidents, left ventricular dysfunction and hypertrophy, and the like. One embodiment of this invention involves administering the peptide, e.g., angiotensin-(1-9) retroinversa, to a patient with any of the above-described cardiovascular diseases.

[0046] As used herein, the method for reducing tissue remodeling comprises reversing, inhibiting, and / or decreasing cardiovascular (heart and blood vessels), pulmonary, renal, and / or cerebral remodeling in an individual or animal. The term “remodeling” refers to the complex change that organs undergo when subjected to stress conditions. Organs of particular interest in this invention for preventing remodeling by using angiotensin-(1-9) retroinversa are the heart, blood vessels, kidney, and brain, without excluding other organs, which may undergo remodeling and could be treated with angiotensin-(1-9) retroinversa.Remodeling should be understood in its broadest possible sense and involves numerous cellular, biochemical, and / or physiological processes, including any or all of cardiomyocyte hypertrophy, neointimal formation, restenosis, fibroblast hyperplasia, smooth muscle cell hyperplasia, fibrosis, collagen deposition, inflammation, apoptosis, necrosis and / or autophagy, and oxidation. Cardiomyocyte hypertrophy corresponds to the enlargement of cardiomyocytes, with increased intracellular protein content, especially those associated with the contractile machinery, and with the re-expression of fetal proteins such as [3-myosin heavy chain ([3-MHC) and atrial neuropathic factor (ANF). Cardiomyocyte hypertrophy is associated with cardiac hypertrophy.Cardiac hypertrophy corresponds to the growth observed in the heart of high-performance athletes (physiological or benign hypertrophy) or in hypertensive individuals or after a myocardial infarction (pathological hypertrophy). Neointimal formation corresponds to the formation of new, undifferentiated or various types of tissue in blood vessels due to damage or any other cause, including restenosis. Restenosis is the re-narrowing of any blood vessel, for example, the re-narrowing of a coronary artery after angioplasty. Restenosis can be due to many other pathologies and causes. Fibroblast hyperplasia corresponds to an increase in the number of fibroblasts due to increased proliferation. Smooth muscle cell hyperplasia corresponds to an increase in the number of smooth muscle cells due to increased proliferation.The term "fibrosis" refers to the increase in extracellular matrix content in a tissue due to the accumulation of proteins such as collagen, fibronectin, elastin, among others. Fibrosis also involves the proliferation of fibroblasts and their differentiation into myofibroblasts. Oxidative stress is understood as an increase in reactive oxygen species and is caused by an imbalance between the synthesis and degradation of reactive oxygen species. Reactive oxygen species correspond to superoxide anion (Os.*-), hydrogen peroxide (H2O2), hydroxyl radical (OH*), and / or products of these species with other molecules that generate, for example, peroxynitrite (NOO*). The synthesis of reactive oxygen species can be synthesized in the mitochondrial oxygen transport chain, NADPH oxidase, xanthine oxidase, NO synthase, through inorganic reactions such as the Fenton reaction and the Haber-Fenton reaction, among others.Reactive oxygen species degradation mechanisms include natural antioxidants (e.g., vitamin C, alpha tocopherol, uric acid, mannitol) and enzyme systems (e.g., superoxide 10 dismutase, catalase, glutathione peroxidase, among others).

[0047] As used herein, the term "cardioprotection" refers to all phenomena, processes, or mechanisms involved in reducing damage or reducing the death of cardiomyocytes. Apoptosis, necrosis, and autophagy correspond to different types of cell death. In this invention, the terms hypertrophy, neointimal formation, restenosis, hyperplasia, cardioprotection, fibrosis, collagen deposition, inflammation, oxidative stress, apoptosis, necrosis, and autophagy should be understood in their broadest context.

[0048] Accordingly, in further aspects the present invention provides a peptide (e.g., HP-16) or a pharmaceutical composition as defined above, for use in: (i) treating a cardiovascular disease, e.g., a cardiovascular disease as defined above;

[0049] (i) prevent, reverse, inhibit and / or reduce cardiovascular, pulmonary, renal and / or cerebral remodeling, preferably wherein the cardiovascular remodeling comprises cardiac fibrosis, cardiomyocyte hypertrophy, cardiovascular inflammation and / or fibroblast proliferation;

[0050] (iii) induce cardioprotection, preferably by decreasing the size of the myocardial infarction;

[0051] The pharmaceutically acceptable excipient of the present invention should be broadly understood as any component of the pharmaceutical composition other than the active compound, and may refer to a diluent, stabilizer, binder, disintegrant, coating agent, sweetener, flavoring and / or coloring, among others, or a mixture thereof. These excipients are known in the state of the art, such as those reported, for example, in Allen L, Popovich N, Ansel H. (201 1). Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. 9th edition. Lippincott Williams & Wilkins, and Rowe R, Sheskey P, Quinn M. (2009). Handbook of Pharmaceutical Excipients. 6th edition. Pharmaceutical Press, without being limited to those mentioned therein. The specific agents and compounds for each of these functions are evident to a person with knowledge in the state of the art and can be found in multiple publications such as those mentioned above.

[0052] A third object of the present invention corresponds to the use of any of the pharmaceutical compositions or their preferred embodiments described above for the preparation of a medicament useful for preventing and / or treating hypertension; or for the preparation of a medicament useful for reducing vascular vasoconstriction at the cardiovascular, cerebral, pulmonary, and renal levels; or for the preparation of a medicament useful for preventing, reversing, inhibiting, and / or reducing the pathological remodeling of cardiovascular, pulmonary, renal, and / or cerebral tissues and / or inducing cardioprotection.

[0053] A fourth object of the present invention corresponds to a method for preventing and / or treating hypertension that comprises administering to a subject who requires it a therapeutically effective dose of any of the pharmaceutical compositions or their preferred embodiments described above.

[0054] EXAMPLES OF IMPLEMENTATION

[0055] The following examples are intended to illustrate the invention and its preferred embodiments, but under no circumstances should they be considered to restrict the scope of the invention, which will be defined by the tenor of the claims appended hereto.

[0056] Example 1. Obtaining peptides

[0057] The peptide D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1), which corresponds to a fusion of the retro-enantio peptide of angiotensin-(1-9) (D-amino acids, N-terminal to C-terminal direction: D H D F D P D H D Yo D AND D V D R D D (SEQ ID NO: 2)) and the peptide angiotensin-(1-7) (L-amino acids, N-terminal to C-terminal direction: L DL R L V L AND L Yo L H L P (SEQ ID NO: 3) were synthesized by GL-Biochem (Shanghai, China).

[0058] A desired volume of solvent was taken and added to a tube containing alumina. Then, in another tube, the sieve was activated by treating at 50°C for 15 min. Finally, the molecular sieve was dried, and the solvent from the tube containing alumina was added. All solvents used were dried with alumina and molecular sieves.

[0059] Resin treatment: The required amount of resin was weighed into a reactor and washed twice with dichloromethane (DCM) after draining the reactor and adding DCM, allowing 10 min for swelling. The reactor was then drained.

[0060] Coupling of the first amino acid: 1.6 mmol of the Fmoc amino acid was weighed per gram of resin and dissolved in the minimum possible amount of DCM. 3 equivalents (relative to the amino acid) of diisopropylethylamine (DIEA) were added, stirring was carried out for 15 min, another 2 equivalents of DIEA were added and the resin was stirred for 1-2 h. Then, 0.5 mL of methanol was added per gram of resin and the resin was stirred for 5 min. The resin was subsequently washed 3 times with DCM, 2 times with dimethylformamide (DMF) and 2 more times with DCM, and the resin was dried. Substitution determination: 5-10 mg of dry amino acid-resin was weighed and 1 mL of 20% pipehdine (without Triton X-100) was added. It was stirred for 20 min and 30 pL of this solution was taken and diluted with 3 mL of DMF in a quartz cell.The absorbance of the samples was then measured at 290-300 nm in a 25 spectrophotometer (using DMF as blank) and the degree of substitution was calculated with the formula (101 x A) / (7.8 x w) where A = Absorbance and w = mg of resin.

[0061] Synthesis of the second amino acid: The resin was washed with DMF. Fmoc was removed with 20% piperidine / DMF and washed with DMF and then with 30% DMF and DCM. The Kaiser test was performed (with a resin peptide sample). Subsequently, it was washed with DMF. Peptide cleavage was performed by acidolysis with thiofluoroacetic acid (TFA), using triethylsilane and water as scavengers (94:3:3, v / v / v) for 60-90 min. TFA was removed with a stream of N2 and the oily residue was precipitated with dry tert-butyl ether. The crude peptide was recovered by centrifugation and decantation of the tert-butyl ether phase.

[0062] The identity was determined by mass spectrometry on a Microflex MALDI-TOF system (Bruker Daltonics Inc., MA-USA) in positive ion mode using linear detection (FIG. 1 ). The spectrum was obtained by mixing 1:1 the peptide and α-cyano-4-hydroxycinnamic acid (10 mg / mL in 50% v / v acetonitrile and 0.1% v / v formic acid) in a micro scout sample holder plate (Bruker Daltonics Inc., MA-USA). Native Angs were used as identity controls. Spectra acquisition and display were performed with a total of 250 laser hits using mMass version 5.5.0 software. The MALDI-TOF peptide algorithm was used to detect monoisotopic m / z signals in the spectra, using a signal-to-noise ratio of 3.5 and a relative intensity cutoff of 0.5%.

[0063] The purity of the peptides was determined by high-pressure liquid chromatography (HPLC) with a diode array detector (FIG. 2). The peptides were applied to an Inertsustain C18 column with a 5 pm particle size. For separation, a linear gradient of 0.1% trifluoroacetic acid in acetonitrile and water was used at a flow rate of 1 mL / min. For peptide detection, a 190-700 nm scan was applied. Example 2. Vasodilatory effect of the peptide of SEQ ID NO: 1

[0064] Ten-week-old male Wistar Kyoto rats were anesthetized with ketamine (35 mg / kg) and xylazine (7 mg / kg) intraperitoneally. The aortas were removed, dissected of extravascular connective tissue and cut into 3 mm rings in fresh Krebs buffer pH 7.4 (KRB, 120 mM NaCl, 25 mM NaHCO2, 5 mM glucose, 4.8 mM KCl, 2.5 mM CaCl2, 1.2 mM MgSO4, 24 mM EDTA and 1.2 mM KH2PO4) freshly bubbled with 5% CO2 in air. They were then mounted on a wire myograph (DMT 620M) and placed in an organ bath with KRB, pH 7.4 at 37°C with constant bubbling and equilibrated for 30 min at a tension of 1.5 g. The vasodilatory response of D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H LP (SEQ ID NO: 1), which corresponds to a fusion of the retro-enantio peptide of angiotensin-(1-9) (D-amino acids, N-terminal to C-terminal direction: D H D F D P D H D Yo D AND D V D R D D (SEQ ID NO: 2)) and the peptide angiotensin-(1-7) (L-amino acids, N-terminal to C-terminal direction: L D L R L V L AND L Yo L H L P (SEQ ID NO: 3) was evaluated in dose-response curves [10 -18 to 10 -4 M] to these molecules in the baths with aortic rings pre-contracted with phenylephrine 10' 7 M. Carbachol (10') was used as a relaxation control. 6 -10' 4M). Peptides were added at cumulative concentrations to the baths when the vasoconstrictor response to phenylephrine reached its maximum level. Vascular tension was recorded with a PowerLab 8 / 25 amplifier, and data were captured and analyzed using LabChart 7.0 software.

[0065] Ex vivo tests showed that D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1) exerts a significantly greater vasodilatory effect at phentomolar concentrations compared to RI-Ang-(1 -9), which is at picomolar concentrations (FIG. 3).

[0066] Example 3. Vasodilatory efficacy of the peptide of SEQ ID NO: 1

[0067] In this experiment, the percentage of vasodilation achieved by aortic rings when incubated withD H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 ) or retro-enantio of angiotensin-(1 -9) (D-amino acids, N-terminal to C-terminal direction: D H D F D P D H D Yo D AND D V D R D D (SEQ ID NO: 2)) at a concentration of 10' 13 M. D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 ) exerts a maximum relaxation effect of 13.4±1.6% (FIG. 4). While the maximum vasodilation achieved by D H D F D P D H D Yo D AND D V D R DD (SEQ ID NO: 2) was 2.1 ±0.6% at the same concentration (FIG. 4).

[0068] Example 4. Vasodilatory effect of the peptide of SEQ ID NO: 1 in the presence and absence of A779

[0069] Aortic rings with intact endothelium were pre-incubated with Mas receptor blocker (A779, 10' 7 M); then pre-contracted with phenylephrine (10- 7 M) until its maximum contraction and the peptide was added D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 ) or retro-enantio of angiotensin-(1 -9) at increasing concentrations (10 -18 at 10' 4 M). A779 partially modified the vasorelaxation induced by D H D F D P D H D Yo D AND D V D R D D L D L RL V L AND L Yo L H L P (SEQ ID NO: 1). This effect was evident between 10' 18 M-10 -9 M of D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1). At higher concentrations A779 did not modify the vasodilation induced by the peptide D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1, FIG. 5).

[0070] Example 5. Vasodilatory effect of the peptide of SEQ ID NO: 1 in the presence and absence of PD123319

[0071] Aortic rings with intact endothelium were pre-incubated with AT2 receptor blocker (PD123319, 10' 5M) and pre-contracted with phenylephrine (10- 7 M). The peptide of SEQ ID NO: 1 was added in increasing and cumulative concentrations (10 -18 at 10' 4 M). PD123319, exerted a partial blockade of the vasodilatory action of the peptide D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 ) in the range of concentrations used (FIG. 6). At concentrations greater than 10' 11 M of D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 ), PD123319 did not block the vasodilatory effect of D H D F D P D H D Yo D AND D V D RD D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 ) [FIG. 6],

[0072] Example 6. Vasodilatory effect of the peptide of SEQ ID NO: 1 in the presence and absence of Losartan

[0073] Aortic rings with intact endothelium were pre-incubated with and without the AT1 receptor blocker (Losartan, 10' 6 M) and pre-contracted with phenylephrine (10 -7 M). The peptide of SEQ ID NO: 1 was added in increasing and cumulative concentrations (10 -18 at 10' 4 M). The RAT1 blocker, losartan, significantly decreased HP16 vasodilation in the concentration range of 10- 18 M-10' 9 M. At higher concentrations of HP-16, losartan did not modify the vasodilatory response of HP16 (FIG. 7).

[0074] Example 7. Vasodilatory effect of the peptide of SEQ ID NO: 1 in the presence and absence of Losartan, PD123319 and A779

[0075] Aortic rings with intact endothelium were pre-incubated with vehicle or with a mixture of Mas receptor blockers (A779, 10' 5 M), AT1 (Losartan, 10' 5 M) and AT2 (PD123319, 10' 4 M) and pre-contracted with phenylephrine (10 -7 M). The peptide of SEQ ID NO: 1 was added in increasing and cumulative concentrations (10 -18 at 10' 4 M). Pre-incubation with losartan, PD123319 and A779 completely blocked the vasodilatory effect of D H D F D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1, FIG. 8).

[0076] Example 8. Effective concentration of the peptide of SEQ ID NO: 1 that produces 50% of the maximum effect

[0077] The effective concentration of the peptide was calculated D H DF D P D H D Yo D AND D V D R D D L D L R L V L AND L Yo L H L P (SEQ ID NO: 1 and the retro-inverso of angiotensin-(1 -9) SEQ ID NO: 2 which produces 50% of the maximum vasorelaxation effect (ECso). Particularly, the ECso corresponds to the concentration of the peptide at which 50% of the vasodilatory response of aortic rings pre-contracted with phenylephhna 10' is reached 7 M. The results showed that HP16 vasorelaxes at a lower concentration 5.089X10' 12 M (Table 1 ) compared to Rl- Ang-(1 -9) [7.67X10' 11 M, Table 1).

[0078] Table 1. ECso of the angiotensin-(1-9) retro-inverso peptide (RI-Ang-(1-9)) and the peptide of SEQ ID NO: 1 (HP16).

Claims

CLAIMS 1. An agonist peptide of the Mas, AT1 and AT2 receptors, CHARACTERIZED in that it comprises the amino acid sequence of SEQ ID NO:

1.

2. A pharmaceutical composition, CHARACTERIZED in that it includes an agonist peptide of the Mas, AT1 and AT2 receptors comprising the amino acid sequence of SEQ ID NO: 1, and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to claim 2, CHARACTERIZED in that the agonist peptide of the Mas, AT1 and AT2 receptors is found in a concentration between 10' 18 M and 10' 4 M.

4. The pharmaceutical composition according to claim 3, CHARACTERIZED in that the agonist peptide of the Mas, AT1 and AT2 receptors is found in a concentration between 10' 15 M and 10' 13 M.

5. The pharmaceutical composition according to any of claims 2 to 4, CHARACTERIZED in that it additionally comprises a drug selected from the group consisting of an angiotensin converting enzyme (ACE) inhibitor, an AT1 receptor blocker, a Rho kinase inhibitor, a renin inhibitor, calcium L channel antagonists and / or diuretics.

6. The pharmaceutical composition according to claim 5, CHARACTERIZED in that said angiotensin I converting enzyme inhibitor is a drug selected from the group consisting of lisinopril, enalapril, captopril, zofenopril, ramipril, quinapril, perindopril, benazepril and fosinopril; said angiotensin II (AT1) receptor antagonist is a drug selected from the group consisting of valsartan, telmisartan, losartan, irbesartan, olmesartan, candesartan, eprosartan and saralasin; said L calcium channel antagonist is a drug selected from the group consisting of nicardipine, nifedipine, amlodipine, felodipine, nitrendipine, nisoldipine, isradipine, nimodipine, diltiazem, clentiazem, verapamil, gallopamil, anipamil, RO5967, falipamil; Said rho kinase inhibitor is a drug selected from the group consisting of fasudil, hydroxyl-fasudil, 3-(4-pyridi I)-1 H-indole, (S)-(+)-2-methyl-1 -[(4-met¡ l-5-isoqui noli ni I) sulfonyl]homopiperazine, N-(4-pyridyl)-N'-(2,4,6-trichlorophenyl)urea; said diuretic is a drug selected from the group consisting of bendroflumethiazide, benzythiazide, chlorothiazide, chlorthalidone, hydrochlorothiazide, hydroflumethiazide, indapamide, methylclothiazide, metolazone, polythiazide, cinetazone, thchlormethiazide, xipamide, furosemide, torasemide, bumetanide, ethacrynic acid, acetazolamide, dorzolamide, amiloride, thamterene, spironolactone, canrenoate, eplerenone and mannitol; said renin inhibitor is a drug selected from the group consisting of pepstatin, CGP2928, remikiren, enalkiren, zankiren, aliskiren;and the other retroinverse peptide is selected from the group consisting of retroinverse bradykinin and retroinverse AT1 R.; 7. The pharmaceutical composition according to any of claims 2 to 6, CHARACTERIZED in that it is formulated for administration by oral, intravenous, intramuscular, intraperitoneal or continuous infusion via a pump.

8. Use of a peptide agonist of Mas, AT1 and AT2 receptors according to claim 1, CHARACTERIZED in that it is used for the preparation of a medicament useful in the prevention and / or treatment of hypertension, including low-renin hypertension, salt-sensitive hypertension, salt-sensitive hypertension with low renin, primary pulmonary hypertension, thromboembolic pulmonary hypertension; pregnancy-induced hypertension; renovascular hypertension.

9. Use of an agonist peptide of the Mas, AT1 and AT2 receptors according to claim 1, CHARACTERIZED in that it is used for the preparation of a medicament useful for preventing, reversing, inhibiting and / or reducing heart failure, including congestive heart failure, compensated heart failure, decompensated heart failure and the like). Restenosis, cardiac hypertrophy, diastolic dysfunction, coronary artery disease, myocardial infarctions, cerebral infarctions, atherosclerosis, atherogenesis, cerebrovascular disease, angina (including chronic, stable, unstable, and vagrant angina pectoris, aneurysm, ischemic heart disease, cerebral ischemia, myocardial ischemia, thrombosis, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, vascular or nonvascular complications associated with the use of medical devices, wounds associated with the use of medical devices, vascular or nonvascular wall damage, peripheral vascular disease, neointimal hyperplasia after percutaneous transluminal coronary angiography, vascular graft, coronary artery bypass surgery, thromboembolic events, post-angioplasty restenosis, coronary plaque inflammation, hypercholesterolemia, embolism, stroke, shock, arrhythmia,atrial fibrillation or atrial flutter, thrombotic occlusion and cerebrovascular seclusion.

10. Use of an agonist peptide of the Mas, AT1 and AT2 receptors according to claim 1, CHARACTERIZED in that it is used for the preparation of a medicament useful for preventing, reversing, inhibiting and / or reducing vasoconstriction. 1 1. Use of an agonist peptide of the Mas, AT1 and AT2 receptors according to claim 1, CHARACTERIZED in that it is used for the preparation of a medicine useful for preventing, reversing, inhibiting and / or reducing the pathological remodeling of cardiovascular, pulmonary, renal, and / or cerebral tissues.

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